DART studies support clinical programs by clarifying risks to fertility, embryo and fetal development, and prenatal and postnatal development to provide safety data that inform enrollment and contraception guidance for eligible patients. But faster timelines, complex development programs, and changing regulatory frameworks can impact nonclinical development, including DART studies. Here are the five most common pitfalls and practical ways to avoid them.
Pitfall 1: Succumbing to Chemistry, Manufacturing & Controls (CMC) Drift
Conducting DART studies can be complicated by changes in clinical formulations and manufacturing processes early in development. Any CMC modifications can potentially affect exposure and safety data obtained from nonclinical toxicology studies. Bridging PK/TK studies may be required to support safety data if changes to manufacturing processes or formulations occur during clinical development.
IND reviewers want to know if reproductive safety findings apply to the clinical product. If it’s not clear, even well-executed strategies may lose value, leading to tough questions, extra bridging work, or repeated studies.
To sidestep this pitfall:
- Any CMC changes should be evaluated for potential impacts on DART studies.
- Define the critical quality attributes and implement disciplined change control for process updates.
- Agree in advance on what a bridging plan looks like if changes cannot be avoided.
- Coordinate toxicology, bioanalysis, pathology, and CMC-facing comparability expectations into a single, coherent plan.
Pitfall 2: Treating DART as ‘Late-Stage’ and Missing the IND Window
Delays often happen when DART studies are conducted without anticipation when they will be required or even if a specific study is needed for a patient population. If teams treat DART as a late task, they may finalize protocols before handling key clinical controls like eligibility for women of childbearing potential, contraception, pregnancy testing, and monitoring rules. Avoid delays in clinical development by planning when each DART study will be required. Each clinical program is different, and scheduling these studies is critical to support patient enrollment and safety, including contraception requirements.
To maintain IND progress, teams need to clearly explain what is known, what is still uncertain, and how they will handle new uncertainties as more data are generated.
To sidestep this pitfall:
- Align DART timing with the intended patient population and use cases.
- Decide early which data are necessary for programs enrolling women of childbearing potential, using chronic dosing, or pursuing accelerated pathways. Some of these data can be generated in early clinical development.
- Stress-test timelines and coordinate material readiness with study start dates to prevent last-minute delays.
Pitfall 3: Relying on Alternative Tools Without a Defensible Story
ICH S5(R3) supports using scientifically justified methods, so many teams try in vitro models, mechanistic data, and computer-based tools for reproductive risk. Problems come up when these tools are used as shortcuts instead of as part of a structured approach. ICH S5(R3) supports the use of in vitro tests, comparative mechanistic and structural activity data, however, these tools are not substitutes for in vivo studies.
Regulators want an integrated approach for both the IND and NDA. Mechanisms, exposure data, and biologic relevance are critical for assessing potential risks in clinical development.
To avoid this pitfall:
- Establish a weight-of-evidence framework before results are available.
- Begin with the key risk questions, such as fertility effects, embryo-fetal development, placental transfer, delivery and lactation effects, and on- or off-target biology.
- Use in vitro and data-science approaches to support decisions on species selection, dosing, endpoints, and timing of in vivo
Pitfall 4: Using Non-relevant Species or Uninterpretable Exposure
For biologics, the main risk is running DART studies in species that do not reflect human targets or pharmacology.
To avoid this pitfall:
- Make relevance and exposure confirmation explicit design requirements.
- Establish target binding, cross-reactivity, and functional activity in candidate species early, and design DART studies using models that can meaningfully test the mechanism at clinically relevant exposures.
- Treat exposure confirmation, including toxicokinetics and relevant immunogenicity factors, as central to data interpretation.
Pitfall 5: Failing to Clearly Translate DART Risk
Even when all stages of reproduction have been covered by DART studies there can be situations where potential effects on human development and reproduction cannot be completely determined. It is critical for clinical investigators represent all nonclinical findings in the investigator brochure to adequately inform patients of potential risks.
IND reviewers must decide if the sponsor understands the risks well enough to dose humans safely. If the trial plan does not address known issues or uncertainties with a risk-based approach, sponsors may experience delays in IND acceptance which, in turn, delays initiation of the clinical program. This results in lost time and additional costs to address regulatory concerns.
To avoid this pitfall:
- Treat DART as a critical component when planning the clinical program. Flexibility is critical when designing an appropriate DART program to support clinical development.
- Evaluate nonclinical findings that affect the clinical program. This includes enrollment criteria, contraception methods and duration, pregnancy testing procedures, monitoring triggers, and stopping rules.
A Final Word
Early, proactive DART planning turns reproductive risk into manageable clinical controls. It also keeps IND and NDA timelines intact. A trusted lab partner can help reduce risk by aligning CMC comparability, GLP study conduct, bioanalysis/toxicokinetics, and IND-ready reporting into a single, defensible package. This kind of integrated approach helps drug developers and sponsors respond quicker to regulator questions and avoid costly development delays.
